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Projekt Druckansicht

Subretinale Implantation und Verankerung mittels Angiogenese von Polyester-Zellträgern zur retinalen Pigmentepitheltransplantation

Antragstellerinnen / Antragsteller Dr. Kirsten Borchers; Dr. Boris Stanzel
Fachliche Zuordnung Augenheilkunde
Biomaterialien
Förderung Förderung von 2014 bis 2020
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 250537947
 
Erstellungsjahr 2023

Zusammenfassung der Projektergebnisse

We successfully developed a hydrogel-based coating of thin PET-foils, which was functionalized with VEGF (proangiogenic growth factor) and was used to trigger elevated formation of capillaries in the chorioallantoic membrane assay (CAM) in chicken embryos. This means that we were able to produce 10 µm hydrogel films, fixed to 10 µm PET membranes with 1 µm track-etched pores. The hydrogels are based on either crosslinked gelatin methacryloyl, un-modified gelatin or albumin, and functionalized with heparin, which in turn is covalently immobilized within the hydrogel. The dried hydrogel coatings can be shelf-stored. Before use, they were loaded with VEGF solution. VEGF release was of first order and achieved approx. 450 ng over 28 days when loaded with 2 µg per membrane (5 mm x 5 mm). Neoangiogenic effects were proofed after three days on the chicken CAM when loading was increased to 5 µg VEGF per membrane. Interestingly, biofunctionality of the carriers differed depending on the biopolymer: Carbodiimide crosslinked gelatinheparin hydrogels induced formation of additional small blood vessels in the CAM, while methacryl-modified gelatins with methacryl-modified heparin and albumin-heparin coatings failed. We thus proved that it is possible to promote sprouting of blood vessels by means of a coated cell carrier transplant. To our knowledge this is the first 20 µm device to deliver VEGF and RPE cells into neural epithelial tissue (i.e. the subretinal space), as demonstrated in a rabbit animal model. The PET foil carrier used provided enhanced porosity then earlier variants in RPE cell culture, i.e. 1 µm pores and 1,5% porosity, and outer retinal atrophy was shown to be reduced in a surgical rabbit model using the membrane without coating. Moreover, the same animal model demonstrated promising subretinal biocompatibility of the PET cell carrier coated with medical grade gelatin type B-heparin hydrogels. Signals on remodelling of the extracellular matrix, detection of cells involved in angiogenesis and gel decay may suggest some preliminary evidence on neovascularization under the implant. As a limitation, the final implant again induced significant retinal atrophy. A proportion of this retinal atrophy was due to immune reactions from the xenografted human RPE with animals intentionally not suppressed to avoid effects on angiogenesis. We assume that the original permeability of the carrier was reduced by the hydrogelcoating. Despite all described challenges, we successfully implemented the complete assembly, implantation and subsequent subretinal bio-integration of a complex 2nd generation RPE cell carrier featuring GF depot coatings without any serious unexpected suspected adverse reactions in a rabbit model. Signals for a therapeutic angiogenesis with a biofunctionalized coating of an RPE cell carrier are still unclear in the rabbit model particularly because of COVID19 set-backs during critical animal experiments. As a result of the project, we have an alpha version of the 2nd generation RPE cell carrier for subretinal implantation at hand, on which the basic and labor-intensive details of production and neoangiogenic functionalization have already been clarified. Subsequent work can now be carried out in a very targeted manner, so that the hypotheses for a follow-up project are: RPE cells tolerate further significant increase in the porosity of the PET support membrane, when using hydrogelcoated PET membranes. - An improved beta version of RPE/carrier implant induces neo angiogenesis and avoids outer retinal atrophy in rabbits and clinically relevant animal models.

Projektbezogene Publikationen (Auswahl)

 
 

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